Project Summary/Abstract. There are 3.5 million annual cases of Traumatic Brain Injury (TBI)1 in which an individual receives an injury to the head that results in a temporary loss of consciousness (LoC) or alteration of consciousness (AoC).2 By age 25, nearly one-third of young adults will experience repeated TBI (rTBI; i.e., 2 or more injuries resulting in LoC or AoC),3 thereby exacerbating the potential for persistent cognitive and emotional dysfunction that is linked to a variety of psychopathological conditions,4,5 including problematic cannabis use.6-8 Given recent changes to cannabis legality, and associated increases in cannabis use,9 it is critical to understand the apparent link between rTBI and cannabis problems, defined as impairment in social (e.g., difficulty maintaining relationships), occupational (e.g., decreased performance at work or school), or financial (e.g., being unable to pay bills due to substance use) domains as a result of cannabis use. Although several epidemiological surveys have demonstrated that those with a TBI history have increased rates of problematic substance use relative to non-TBI controls little is known about the potential mechanisms explaining this link due to the systematic exclusion of individuals with a rTBI history from nearly all prospective investigations of cannabis use and the exclusion of cannabis users from nearly all prospective studies of rTBI (see Bjork and Grant, 2009 for a review).10 This oversight has left inadequate answers to two concerning questions: Does rTBI history predict greater cannabis-related problems and, if so, what are the explanatory mechanisms of this vulnerability? Consistent with a central focus of NIDA on identifying explanatory processes of vulnerability in high-risk populations, the present study proposes a novel prospective investigation that tests whether rTBI is associated with cannabis-related problems. We will then test putative indirect pathways via which rTBI may increase cannabis problems by utilizing event-related potential (ERP) methodology, notably the Late Positive Potential (LPP) amplitude while viewing and down-regulating responses to emotional images and the N2/P3 component amplitudes during a response inhibition task. The first specific aim of the proposed study is to test if rTBI has a direct relationship with cannabis problems. This will be accomplished through both cross-sectional (i.e., baseline) and prospective cannabis problems, as assessed via self-report and clinical interview. The second specific aim is to test the indirect effect of rTBI on cannabis problems through heightened emotion reactivity (i.e., greater LPP while viewing cannabis cues and threatening images). The third specific aim is to test the indirect effect of rTBI on cannabis problems through emotion regulation difficulties (i.e., greater LPP while volitionally regulating cannabis craving, greater LPP while cognitively re-appraising threatening images). Lastly, the fourth specific aim is to test the indirect effect of rTBI on cannabis problems through deficits in inhibitory control (i.e., blunted N2 and P3 component amplitudes during response inhibition).